IN VIVO SIGNALING OF THE ERYTHROPOIETIN RECEPTOR

描述（申请人描述）： 促红细胞生成素受体（EPO-R）信号传导对于分化至关重要， 成熟红系祖细胞的增殖和存活。 EPO-R信号传导功能障碍导致恶性肿瘤和其他疾病 红细胞白血病和真性红细胞增多症。 研究 在过去的几年里，已经强调了信号通路 由生长因子受体和酪氨酸激酶受体激活的， 是多余的，被许多受体共享。 他们还指出， 缺乏对受体信号传导的理解， 生理环境 本建议的总体目标是 克服缺乏关于调节EPO-R的机制的信息 正常发育过程中的信号。 本提案中概述的研究旨在调查 MAP-激酶通路（ERK，JNK，p38）的参与和作用 利用逆转录病毒基因转移到胎肝细胞中的红系发育 来自EPO-R基因敲除小鼠。 这些小鼠在胚胎中死于严重的贫血， 晚期红系祖细胞分化的缺乏。 的 申请人将研究JNK和p38的潜在激活是否 (ERK已知由EPO-R接合激活）响应于 EPO-R参与对于细胞结果如增殖是重要的， 红系细胞的分化或存活。 她也在克隆小说 细胞因子诱导的含SH 2（CIS）样基因，可能负性 调节EPO-R信号传导。 此外，她还将调查 在红系恶性肿瘤中， 真性红细胞增多症 在一个相关的项目中，她将研究体内 EPO-R酪氨酸磷酸化的作用。 在这个过程中，她将 利用胎肝细胞建立体内嵌合动物模型系统 从用特异性EPO-R突变体逆转录病毒转导的EPO-R-/-小鼠， 在致死辐射的成年小鼠中重建红细胞生成。 EPO-R信号转导及其机制的分子研究进展 红系血液疾病和恶性肿瘤中的调节异常对于 开发新的治疗方法，如纠正 通过基因治疗来修复缺陷。

DESCRIPTION (Applicant's Description): Erythropoietin-Receptor (EPO-R) signaling is crucial for differentiation, proliferation and survival of mature erythroid progenitor cells. Dysfunction of EPO-R signaling results in malignancies and other disorders of erythroid cells such as erythroleukemias and polycythemia vera. Studies during the past several years have emphasized that signaling pathways activated by growth factor receptors and tyrosine kinase receptors are redundant and shared by many receptors. They have also pointed out the absence of understanding of receptor signaling in their primary physiological setting. The overall objective of this proposal is to overcome this lack of information regarding mechanisms that regulate EPO-R signaling during normal development. The studies outlined in the present proposal are aimed to investigate the involvement and the role of MAP-kinase pathways (ERK, JNK, p38) during erythroid development using retroviral gene transfer into fetal liver cells from EPO-R knock-out mice. These mice die in embryo from severe anemia, due to an absence of differentiation of late erythroid progenitor cells. The applicant will investigate whether the potential activation of JNK and p38 (ERK is known to be activated by the EPO-R engagement) in response to the EPO-R engagement is important for cellular outcomes such as proliferation, differentiation or survival of erythroid cells. She is also cloning novel Cytokine-Inducible-SH2-containing(CIS)-Like genes which may negatively regulate EPO-R signaling. In addition, she will investigate the involvement of the negative regulators of EPO-R signaling in erythroid malignancies such as polycythemia vera. In a related project she will investigate the in vivo role of tyrosine phosphorylation of the EPO-R. In this process she will establish an in vivo chimeric animal model system using fetal liver cells from E P O-R-/- mice retrovirally transduced with specific EPO-R mutants to reconstitute erythropoiesis in lethally irradiated adult mice. Molecular understanding of EPO-R signaling and its mechanisms of dysregulation in erythroid blood disorders and malignancies is essential for development of novel therapeutic approaches such as the ones that correct the defect by gene therapy.